Micturition is a complex neuromuscular process. Although control mechanisms have been identified at several levels of the central nervous system, the final pathway fin micturition control is the autonomic innervation of the urinary bladder and related structures. During the present funding period, we have contributed substantially to understanding the physiology, pharmacology, and morphology of the lower urinary tract. We have developed, standardized, and evaluated a number of experimental animal models of partial outlet obstruction (including the rabbit, rat, and cat). Based on our studies, the bladder's progressive response to partial outlet obstruction can be divided into three distinct phases: l) An initial response to surgical induction of partial outlet obstruction (days 1--14). During this phase there are substantial alterations in bladder mass, pharmacology, and physiology. 2) Compensated bladder function immediately follows the "initial phase" and lasts an indefinite, variable period of time. This period is characterized by relatively stable bladder mass, and stable contractile responses (which may be above control values) to field, bethanechol, and KCl stimulation. 3) Finally, at some point, functional ability to empty degenerates and the bladder becomes "decompensated". The decompensated phase is characterized by progressive deterioration in contractile and functional status, a rapid increase in mass, and a progressive decrease in the volume fraction of smooth muscle elements within the bladder. The end result is either an organ with a thick fibrous wall, low capacity, poor compliance, and little or no contractile function; or, a dilated bladder with a thin fibrous wall, high capacity and little or no contractile function. In separate experiments, we have characterized the response to diuresis-induced hypertrophy of the bladder. Our working hypothesis is: Any stress, whether physiological, pathophysiological, or experimental, that either increases urethral resistance or increases urine volume induce a progressive increase in bladder mass. The increase in bladder mass secondary to partial outlet obstruction is a protective response to the increased intravesical pressure (and resultant distension) required to empty the bladder: the result is a bladder characterized by decreased compliance, increased tensile strength, and impaired function (ability to generate pressure, sustain pressure, and/or empty). The increase in bladder mass secondary to diuresis involves no increase in urethral resistance and no change in micturition pressure. The result is a fully functional bladder with an enhanced ability to contract and empty. The specific aims of our current competitive grant renewal include the following: a. Determine the sequela of events that result in the shift from compensated bladder function to decompensated function. b. Determine the point, in the above sequella, at which release of partial outlet obstruction does not reverse the functional changes which it induces. c. Determine the cellular factors that participate in the functional responses observed during chronic diuresis. d. Determine whether bladder structure and function return to control levels following the termination of diuresis. In addition to the studies on chronic partial outlet obstruction and diureses described above, we will determine the effect of partial outlet obstruction, acute overdistension, and diuresis on 14C-adenine and 14C- creatine incorporation into the cellular high energy phosphate pool. Utilizing 3H-thymidine incorporation into DNA, we will determine if these three experimental protocols result in hyperplasia of specific cell types within the bladder.